Nitric oxide is produced in mammalian cells from L-arginine by the action of specific nitric oxide synthases (NOSs). These enzymes fall into two distinct classes--constitutive NOS (cNOS) and inducible NOS (iNOS). At the present time, two constitutive NOSs and one inducible NOS have been identified. Of the constitutive NOSs, an endothelial enzyme (ecNOS) is involved with smooth muscle relaxation and the regulation of blood pressure and blood flow, whereas the neuronal enzyme (ncNOS) serves as a neurotransmitter and appears to be involved in the regulation of various biological functions such as cerebral ischaemia. Inducible NOS has been implicated in the pathogenesis of inflammatory diseases. Specific regulation of these enzymes should therefore offer considerable potential in the treatment of a wide variety of disease states.
Compounds of various structures have been described as inhibitors of NOS and their use in therapy has been claimed. See, for example, WO 95/09619 (The Wellcome Foundation) and WO 95/11231 (G. D. Searle). The applicant has previously disclosed in WO 95/05363 and WO 96/01817 amidine derivatives which are NOS inhibitors which display some selectivity for inhibition of the neuronal enzyme, ncNOS.
We now disclose a group of amidines that are within the generic scope of WO 96/01817, but which are not specifically exemplified in WO 96/01817. These compounds display surprisingly advantageous properties and are the subject of the present application.